Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Neuroscience

Supervisor

Dr. Robert C. Cumming

Abstract

Maintenance of telomere length during cell division is dependent on the catalytic subunit telomerase reverse transcriptase (TERT), which adds TTAGGG repeats to the ends of chromosomes to prevent telomere shortening during DNA replication. However, non-telomeric roles of TERT have emerged under oxidative stress whereby TERT translocates from the nucleus to the mitochondria and protects against mitochondrial dysfunction through a poorly defined mechanism. A major pathological feature of Alzheimer’s Disease (AD) is the progressive accumulation of amyloid-beta (Aβ) peptide within the cortex and hippocampus. Aβ can directly interfere with mitochondrial respiration and promote mitochondrial dysfunction, ROS production, and neuronal cell death. A shift in metabolism away from oxidative phosphorylation towards aerobic glycolysis has been shown to confer neuroprotection against A toxicity. Hence, it was hypothesized that elevated TERT expression can protect neurons from mitochondrial dysfunction and Aβ toxicity via metabolic reprogramming. TERT overexpression in the neuronal cell line HT22 promoted a shift towards aerobic glycolysis by altering levels of glycolytic enzymes following exposure to H2O2 and Aβ. Furthermore, TERT overexpression decreased mitochondrial ROS levels and improved cell viability during oxidative stress. Following exposure to H2O2 and Aβ, TERT translocation to the cytoplasm and mitochondria was observed. The results from this study suggest that TERT may be a therapeutic target for potential treatment of AD.

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